Stabilized aqueous amide antimicrobial composition

ABSTRACT

Aqueous antimicrobial compositions which comprise a halogenated amide antimicrobial, such as 2,2-dibromonitrilopropionamide, a water miscible organic solvent such as a straight chain polyalkylene glycol (e.g., polyethylene glycol 200) or an ether thereof (e.g., a mono- or di-lower alkyl and/or phenyl ether) and water are stabilized against decomposition of the halogenated amide antimicrobial by the addition of an azine or nitrile stabilizer, such as s-triazine-2,4,6-triol (i.e., cyanuric acid), 2-chloro-4,6-(ethylamino)-s-triazine, succinonitrile, cyanoguanadine, etc. The compositions, so stabilized, exhibit reduced rates of decomposition of the halogenated amide antimicrobial relative to the corresponding non-stabilized aqueous compositions.

BACKGROUND OF THE INVENTION

This invention relates to stabilized aqueous antimicrobial compositionswhich comprise a halogenated amide as the active (i.e., antimicrobial)ingredient and to processes for their preparation.

Halogenated amides such as 2,2-dibromonitrilopropionamide are useful asantimicrobials in various applications. See, for example, Nolan et al.,U.S. Pat. No. 2,419,888; Schmidt et al., U.S. Pat. No. 3,493,658; andCIBA S.A. Belgian Pat. No. 668,336. Certain halogenated amides areuseful in the finishing of textiles, as taught by Chance et al., U.S.Pat. Nos. 3,350,164 and 3,403,174. Others are useful as slimicides inaqueous systems such as paper pulp and cooling towers and as sterilizingagents for drycleaning fluids. See, for example, Wolf, U.S. Pat. No.3,647,610; Wolf, U.S. Pat. No. 3,649,166; Wolf et al.,"2,2-Dibromo-3-Nitrilopropionamide, A Compound with SlimicidalActivity", Applied Microbiology, Vol. 24, No. 4, pp. 581-584 (1972); andMoyle et al., U.S. Pat. No. 3,928,575.

In the storage, shipment and use of such antimicrobial agents, it isoften desirable to employ the antimicrobial agent in the form of aliquid concentrate composition wherein the halogenated amideantimicrobial is dissolved in a mixture of an organic solvent and water.However, the presence of water is such compositions often acceleratedecomposition of the halogenated amide antimicrobial. See, for example,U.S. Pat. No. 3,689,660 and "Rates and Products of Decomposition of2,2-Dibromo-3-Nitrilopropionamide", Exner et al., J. Agr. Food Chem.,Vol. 21, No. 5, pp. 838-842 (1973). Accordingly, in order to obtainadequate stability for many purposes, it has heretofore been necessaryto resort to essentially anhydrous liquid concentrate compositions andit has therefore been necessary to essentially exclude water from theingredients used in the preparation thereof.

Consequently, it is desirable to provide a means of reducing the adverseimpact of water upon the aforementioned liquid concentrate compositionsand to thereby provide both aqueous halogenated amide antimicrobialcompositions having improved stability and simplified economicalprocesses for the preparation of stable liquid concentrate compositions.

SUMMARY OF THE INVENTION

It has now been found that the rate of decomposition of the halogenatedamide antimicrobial in the aforementioned aqueous liquid concentratecompositions is substantially reduced by the addition of an azine or anitrile stabilizer. Thus, in one aspect the instant invention is astabilized aqueous antimicrobial composition which comprises (1) a watermiscible organic solvent; (2) water; (3) a halogenated amideantimicrobial; and (4) a stabilizing amount of an azine stabilizer, or anitrile stabilizer, which is different from the halogenated amideantimicrobial. Typically, such composition has a pH of from about 2 toabout 5 (preferably from about 3 to about 4).

In another aspect the instant invention is a process for preparing anaqueous halogenated amide antimicrobial composition wherein the aqueouscomponent of such composition comprises the aqueous reaction medium inwhich the halogenated amide antimicrobial was prepared. Such processcomprises the steps of:

(a) preparing the halogenated amide antimicrobial by the acid catalyzedreaction of a non-halogenated amide with halogen in aqueous solution;

(b) dissolving the resulting aqueous reaction mixture in a watermiscible organic solvent; and

(c) adding to the reaction mixture, or to the water miscible organicsolvent solution thereof, a stabilizing amount of an azine or a nitrilestabilizer which is different from the halogenated amide antimicrobial.

Typically, the aforementioned process also involves a pH adjustment stepsuch that the composition resulting from such process has a pH of fromabout 2 to about 5, preferably from about 3 to about 4.

As used herein, the term "water miscible" means that the organic solventis soluble in water (i.e., mixes or blends uniformly with water) atleast to the degree required to achieve the desired solvent to waterratio in the aqueous composition and preferably the organic solvent issoluble in water in all proportions.

The terms "antimicrobial compound" and "halogenated amide antimicrobial"are used interchangeably herein and refer to halogenated amides whichfunction as biocides (i.e., compounds which inhibit the growth of, orkills, microorganisms such as bacteria, molds, slimes, fungi, etc.).

As used herein, the term "azine stabilizer" refers to a saturatedaliphatic or a saturated alicyclic compound containing a moiety of theformula >C═N-- wherein "saturated" refers to freedom from carbon tocarbon unsaturation. The term "nitrile stabilizer" refers to a saturatedaliphatic or saturated alicyclic compound containing a moiety of theformula --C.tbd.N wherein "saturated" has the aforesaid meaning.

The term "stabilizing amount" as employed herein refers to an amount ofstabilizer sufficient to measurably reduce the decomposition rate of thehalogenated amide antimicrobial in the aqueous antimicrobialcomposition. The aforementioned reduction in the decomposition rate ofthe halogenated amide antimicrobial is, of course, relative to thedecomposition rate encountered with a corresponding aqueousantimicrobial composition in the absence of the stabilizer under thesame test conditions. Such reduction is deemed to be "measurable" if itis detectible (and reproducible) by the iodometric test method which isdescribed hereinafter in conjunction with the working examples.

The aqueous antimicrobial compositions of the invention are useful asslimicides in aqueous systems such as paper pulping processes andcooling towers and as sterilizing agents for drycleaning fluids. Suchcompositions exhibit improved stability toward decomposition of thehalogenated amide antimicrobial for extended periods under a widevariety of storage, packaging and handling conditions. They are easilyhandled and can be employed in the above applications pursuant toconventional techniques such as those described in U.S. Pat. No.3,689,660.

The indicated process for preparing the aqueous antimicrobialcomposition is advantageous in that suitably stable compositions can beprepared without separation of the halogenated amide antimicrobial fromthe aqueous medium in which it was prepared.

DETAILED DESCRIPTION OF THE INVENTION

Halogenated amide antimicrobials employed in the practice of thisinvention are alpha-haloamides; that is, compounds which contain anamide functionality (i.e., a moiety of the formula --C(O)--N<) and whichhave at least one halogen atom on a carbon atom located adjacent to(i.e., in the alpha position relative to) the carbonyl group (i.e., the--C(O)-- group) of such amide functionality. Advantageously, suchhalogenated amide antimicrobials are halogenated nitrilopropionamides orhalogenated malonic diamides having the formula: ##STR1## wherein: X ishydrogen, halogen or a cyano radical, i.e., --C.tbd.N, (preferablyhydrogen, chlorine or bromine);

each R group is independently hydrogen, a monovalent "saturatedhydrocarbon radical" or an inertly substituted monovalent "saturatedhydrocarbon radical" or the two R groups are, jointly, a divalent"saturated hydrocarbon radical", or an inertly substituted divalent"saturated hydrocarbon radical", which, taken with the adjacent nitrogenatom, forms a heterocyclic ring having from 4 to about 10 ring members;and

R₁ is a cyano radical (i.e., --C.tbd.N) or an amido radical having theformula: ##STR2## wherein R is as hereinbefore defined. (Preferably R₁is a cyano radical.)

As used herein, the term "saturated hydrocarbon radical" refers to ahydrocarbon radical which is free from aliphatic carbon to carbonunsaturation. Thus, such term includes radicals such as alkyl,cycloalkyl, aryl, alkylaryl, arylalkyl, cycloalkylaryl, etc., andexcludes radicals such as alkenyl, cycloalkenyl, alkynyl and the like.

As used herein, the term "inertly substituted saturated hydrocarbonradical" refers to a "saturated hydrocarbon radical" having one or morechain linkage or substituent which is "inert" in the sense that suchchain linkage or substituent does not readily react with the ingredientsof the aqueous antimicrobial composition. Suitable inertly substitutedsaturated hydrocarbon radicals thus include, for example, haloalkyl,haloaryl, halocycloalkyl, aminoalkyl, aminoaryl, aminocycloalkyl,hydroxyalkyl, hydroxyaryl, hydroxycycloalkyl, cyanoalkyl, cyanoaryl,cyanocycloalkyl, and the like.

The aforementioned halogenated amide antimicrobials of the formula Ithus include brominated nitrilopropionamides (i.e., compounds of theformula I wherein R₁ is a cyano radical), such as2-bromo-3-nitrilopropionamide, 2-bromo-2,3-dinitrilopropionamide,2,2-dibromo-3-nitrilopropionamide,N-(n-butyl)-2-bromo-3-nitrilopropionamide;N,N-dimethyl-2,2-dibromo-3-nitrilopropionamide,2-chloro-2-bromo-3-nitrilopropionamide,N-(n-propyl)-2-iodo-2-bromo-3-nitrilopropionamide,N-methyl-N-ethyl-2-fluoro-2-bromo-3-nitrilopropionamide,N-phenyl-2-cyano-2-bromo-3-nitrilopropionamide,N-cyclohexyl-2,2-dibromo-3-nitrilopropionamide,N-benzyl-2-bromo-3-nitrilopropionamide,N-(2,2-dibromo-3-nitrilopropionoyl)-piperidine and the like.

The aforementioned halogenated amide antimicrobials of the formula Ialso include mono- and di-bromomalonic diamides (i.e., compounds of theformula I wherein R₁ is an amido radical as hereinbefore described),such as 2-bromomalonic diamide, 2,2-dibromomalonic diamide,N-methyl-N'-ethyl-2-chloro-2-bromomalonic diamide,N-phenyl-2-iodo-2-bromomalonic diamide, and the like.

Among the aforementioned halogenated amide antimicrobials, thosewherein, in the formula I, R₁ is a cyano radical, X is hydrogen,chlorine or bromine and each R is independently hydrogen, lower alkyl(e.g., an alkyl group of from 1 to about 6 carbon atoms) or phenyl arepreferred, especially those of the formula I wherein each Rindependently is hydrogen or methyl and X is hydrogen or bromine. Suchhalogenated amide antimicrobials include 2-bromo-3-nitrilopropionamide,2,2-dibromo-3-nitrilopropionamide,N-methyl-2-bromo-3-nitrilopropionamide,N-phenyl-2-bromo-2-chloro-3-nitrilopropionamide,N-methyl-2,2-dibromo-3-nitrilo-propionamide,N,N-dimethyl-2-bromo-3-nitrilopropionamide,N,N-diethyl-2,2-dibromo-3-nitrilopropionamide, andN,N-dimethyl-2,2-dibromo-3-nitrilopropionamide.

Also of particular interest are the dibrominated nitrilopropionamides(i.e., the halogenated amide antimicrobials of the formula I wherein Xis bromine and R₁ is cyano) wherein each R independently is hydrogen,lower alkyl or phenyl. Such compounds include2,2-dibromo-3-nitrilopropionamide,N-(n-butyl)-2,2-dibromo-3-nitrilopropionamide,N,N-dimethyl-2,2-dibromo-3-nitrilopropionamide,N-phenyl-N-methyl-2,2-dibromo-3-nitrilopropionamide and the like;especially 2,2-dibromo-3-nitrilopropionamide.

The aqueous antimicrobial compositions of the invention normally containfrom about 1 to about 25 percent by weight of the hereinbefore describedhalogenated amide antimicrobial based upon the total weight of thecomposition. However, the decomposition of the halogenated amideantimicrobials has been observed to be more pronounced when the aqueouscompositions contain less than about 20 percent by weight of theantimicrobial on a total weight basis. Thus, stabilized aqueousantimicrobial compositions which, by virtue of the relatively morepronounced benefits of stabilization, are of particular interestcomprise from about 1 to about 15, preferably from about 1 to about 10,most preferably from about 1 to about 5, weight percent of the totalcomposition.

In the composition of this invention, the aforementioned halogenatedamide antimicrobial is dissolved in a mixture of water and a watermiscible organic solvent. Suitable organic solvents include any watermiscible organic solvent in which the halogenated amide antimicrobial isat least partially soluble. Preferably the organic solvent is one inwhich the halogenated amide antimicrobial is soluble at normal roomtemperature (i.e., from about 20° to about 25° C.) to the extent of atleast about 5 parts by weight of the antimicrobial in about 95 parts byweight of the solvent. The most preferred water miscible organicsolvents are those in which the antimicrobial is soluble to the extentof at least about 10 (especially at least about 20) parts by weight ofthe antimicrobial in about 80 parts by weight of the solvent at normalroom temperatures (i.e., from about 20° to about 25° C.).

Advantageously, the organic solvent is a polyalkylene glycol or an etherthereof, especially a normally liquid straight chain polyalkylene glycolor a mono- or di-saturated hydrocarbyl ether thereof wherein the term"saturated hydrocarbyl" refers to a monovalent saturated hydrocarbonradical as hereinbefore defined.

Generally, such polyalkylene glycols and polyalkylene glycol ethers havea weight average molecular weight (Mw) of from about 75 to about 1000.Such average molecular weights are hereinafter designated for theparticular glycols involved by placing a numeral representing the weightaverage molecular weight after the glycol name.

Of particular interest in the practice of the invention are thepolyalkylene glycols of the ethylene, trimethylene or tetramethyleneseries and the mono- and di-lower (e.g., containing from 1 to about 6carbon atoms) saturated hydrocarbyl ethers thereof. Examples of suchparticularly advantageous solvents include polyethylene glycols,trimethylene glycols, tetramethylene glycols and the mono- and di-lowersaturated hydrocarbyl (e.g., C₁ to about C₆ alkyl and phenyl) ethers ofsuch glycols.

Examples of the aforementioned polyalkylene glycols and ethers include1,4-butanediol, triethylene glycol, polyethylene glycol 200,tetraethylene glycol, polyethylene glycol 400, diethylene glycoldimethyl ether, diethylene glycol phenyl ether, diethylene glycol ethylphenyl ether, polytrimethylene glycol 200, diethylene glycol,triethylene glycol methyl ether and polyethylene glycol 600.

Preferably, the polyalkylene glycol or ether ingredient is apolyethylene glycol, or a mixture of polyethylene glycols, having Mw offrom about 175 to about 250. Most preferably the polyalkylene glycolingredient is polyethylene glycol 200.

The amount of the aforementioned water miscible organic solvent employedin the practice of the invention is not particularly critical.Advantageously, however, a sufficient amount is employed to preventprecipitation of the halogenated amide antimicrobial during shipping,storage and use of the aqueous antimicrobial composition. The amount ofthe organic solvent desirably employed will thus depend upon suchfactors as the solubility of the halogenated amide antimicrobial in theorganic solvent, the desired concentration of the halogenated amideantimicrobial in the composition, and the like. However, as a generalrule the organic solvent constitutes from about 5 to about 90,preferably from about 10 to about 80, more preferably from about 25 toabout 75, most preferably from about 35 to about 70, percent by weightof the total antimicrobial composition.

As has been noted, any of the aforementioned water miscible organicsolvents can be suitably employed in the practice of this invention todissolve the aforementioned halogenated amide antimicrobial. However, ithas been found (and such finding constitutes the subject matter of acommonly owned application by George A. Burk, Charles A. Wilson andCharles E. Reineke, filed even date herewith) that the aforementionedproblem of halogenated amide decomposition under aqueous conditions issubstantially more pronounced in the presence of salts of organic acidsand/or glycols having a molecular weight of less than about 70 grams permole; both of which, for example, are potentially common minorimpurities in many commercially available unpurified polyalkyleneglycols and ethers thereof. Thus, the benefits attributable to theherein disclosed stabilizers are relatively more pronounced in thosestabilized aqueous antimicrobial compositions which employ commercialgrades of organic solvents containing the aforementioned impurities orwhich contain such impurities from some other source.

The amount of water contained by the aqueous antimicrobial compositionof the invention is likewise not particularly critical to the practiceof the invention. However, as a general rule the compositions of theinvention employ water in an amount of from about 5 to about 90,preferably from about 10 to about 85, more preferably from about 15 toabout 70, most preferably from about 20 to about 60 weight percent basedupon the weight of the total antimicrobial composition.

The azine or nitrile stabilizer employed in the practice of thisinvention is a saturated (i.e., free of carbon to carbon unsaturation)aliphatic, or saturated alicyclic, compound which contains a moiety ofthe formula: >C═N--; a moiety of the formula: --C.tbd.N; or acombination of such moieties; and which is different from thehalogenated amide antimicrobial employed. Examples of such stabilizersinclude cyanuric acid (i.e., s-triazine-2,4,6-triol),2-chloro-4,6-(ethylamino)-s-triazine, succinonitrile, cyanoguanidine,and the like.

The hereinbefore described azine or nitrile stabilizer is employed inthe practice of the invention in a "stabilizing amount", which term isdefined hereinbefore. Advantageously, such stabilizer is employed in anamount sufficient to reduce by at least about 20 percent (preferably byat least about 30 percent and most preferably by at least about 40percent) the amount of antimicrobial compound which decomposes duringabout 15 days (preferably about 30 days) of storage at 50° C. Suchdecomposition reduction is, of course, relative to that which occursunder the same conditions in the absence of the aforementionedstabilizer. In quantitative terms, the amount of stabilizer needed toachieve the desired degree of stabilization can vary depending upon theremainder of the composition (i.e., the identity and concentration ofthe other ingredients in the particular composition involved) and uponthe particular stabilizer employed. However, as a general rule thestabilizer constitutes between about 0.05 and about 10, preferablybetween about 0.1 and about 5, most preferably between about 0.5 andabout 2, percent by weight of the total composition.

In addition to the hereinbefore defined ingredients, the aqueousantimicrobial composition of the invention can optionally contain otheringredients. Such optional ingredients can be inert in the sense thatthey neither inhibit nor accelerate decomposition of the antimicrobialcompound. Alternatively, such optional ingredients can themselves bestabilizers for the halogenated amide antimicrobial. Thus, for example,the stabilized aqueous antimicrobial composition of the invention can,in addition to the aforementioned azine or nitrile stabilizer, furthercomprise other compounds which are stabilizers in their own right asdisclosed in commonly owned applications filed even date herewith. Suchoptional additional stabilizers include acids or anhydrides (e.g.,acetic acid, ethylenediaminetetraacetic acid, succinic acid, succinicanhydride, glycolic acid, etc.) as disclosed by George A. Burk;carbamoyl or sulfamoyl compounds (e.g., N-methyl urea, N,N-diethyl urea,biuret, sulfamide, oxamide, N,N-dimethylformamide, caprolactam,N-methyl-2-pyrrolidone, dimethylhydantoin, succinimide, etc.) asdisclosed by George A. Burk and Charles E. Reineke; cyclic ethers (e.g.,1,4-dioxane, tetrahydrofuran, 1,3,5-trioxane, N-methyl morpholine, etc.)as disclosed by George A. Burk and Charles A. Wilson; aldehydes (e.g.,formaldehyde, paraformaldehyde, vanillin, etc.) as disclosed by GeorgeA. Burk, Charles A. Wilson and Charles E. Reineke; and quaternary salts(e.g., methyl triphenyl phosphonium bromide, n-C₁₂ -C₁₈ alkyl dimethylbenzyl ammonium chloride, etc.) as disclosed by George A. Burk. Theamount of such additional stabilizer which is optionally employed variesdepending upon a number of factors, such as the identity and amounts ofthe specific ingredients involved. However, when such additionalstabilizer is employed, it is generally used in an amount as a generalrule between about 0.1 and about 2 (preferably between about 0.2 andabout 1) percent by weight based upon the total weight of theantimicrobial composition.

The order of combination of the hereinbefore described ingredients isnot critical to the obtention of a decreased decomposition rate relativeto that obtained with the corresponding non-stabilized composition.However, in order to avoid excessive amounts of decomposition prior tostabilization, it is generally desirable to avoid prolonged exposure ofthe antimicrobial compound to the water in the composition prior toaddition of the stabilizer thereto. Similarly, it is generallydesirable, in order to retain optimum antimicrobial activity, toprepare, store, transport and handle the stabilized compositions of theinvention at the lowest practicable temperature (normally ambienttemperature). Similarly, it is desirable that the pH of the compositionsbe maintained at a value between about 2 and about 5 (preferably betweenabout 3 and about 4) since the decomposition of the antimicrobial underaqueous conditions (both with and without stabilization) is typicallyminimized within such pH range.

As has been noted, the hereinbefore described stabilizers have beenfound to reduce the halogenated amide antimicrobial decomposition ratein a water-organic solvent mixture. A particularly beneficial result ofsuch phenomenon is that suitably stable halogenated amide antimicrobialcompositions can be prepared directly from a mixture of theantimicrobial and the aqueous reaction medium in which it was prepared.Specifically, separation of the halogenated amide antimicrobial from itsaqueous reaction medium is conveniently eliminated by incorporating suchreaction medium into the antimicrobial composition and by counteractingthe adverse impact of the water thereby introduced into such compositionby adding the aforementioned azine or nitrile stabilizer.

Thus, in one aspect this invention is a process for preparing theaforementioned stabilized aqueous antimicrobial compositions, whichprocess comprises the steps of (a) preparing the halogenated amideantimicrobial by the acid catalyzed reaction of the correspondingnon-halogenated amide with halogen in aqueous solution; (b) dissolvingthe resulting aqueous reaction mixture in the hereinbefore describedwater miscible organic solvent; and (c) adding to the reaction mixture,or to the water soluble organic solvent solution thereof, a stabilizingamount of the aforementioned azine or nitrile stabilizer. Typically, theaforementioned process also comprises an additional step in which the pHof the reaction mixture, the organic solvent solution, or the stabilizedorganic solvent solution is adjusted such that the pH of theantimicrobial composition is from about 2 to about 5, preferably fromabout 3 to about 4. Preferably, such pH adjustment step is performedfollowing preparation of the halogenated amide and prior to dissolutionof the reaction mixture in the organic solvent. In such instance,adjustment of the pH to a value of from about 5 to about 7 (preferablyfrom about 5.5 to about 6.5) prior to dissolution typically provides theantimicrobial composition with a pH within the desired range followingthe dissolution step.

The particular reagent employed in the aforementioned pH adjustment stepis not particularly critical. However, as a general rule, alkali metalor alkaline earth metal carbonates or bicarbonates (especially sodiumcarbonate) are advantageously employed.

The preparation of the halogenated amide antimicrobial (i.e., step (a)above) can be accomplished in any convenient conventional manner. Thus,for example, the halogenated amide antimicrobial can be prepared by theacid catalyzed reaction of the corresponding non-halogenated amide(e.g., cyanoacetamide, malonic diamide, and N-substituted derivativesthereof) with halogen (especially bromine) in aqueous solution,preferably at a temperature of less than about 40° C. and preferably ata hydrogen halide (which is a reaction by-product) concentration of lessthan about 20 weight percent on a total weight basis.

Preferably, however, the initial step of such process is performedpursuant to the improved procedure which is disclosed by U.S. Pat. No.3,751,444. In such preferred process for preparing the halogenated amideantimicrobial, the improved aspect comprises introducing a water-solublebromate into the aqueous reaction medium. Further details relating tothe practice of such preferred initial step are found in U.S. Pat. No.3,751,444, the disclosure of which is hereby incorporated by reference.

After the halogenated amide antimicrobial has been prepared in theaforementioned manner, the resulting reaction mixture is dissolved inthe hereinbefore described organic solvent. Such dissolution step isperformed either before or after addition of the stabilizer and withoutisolation of the halogenated amide antimicrobial from the aqueousreaction medium. Any of the hereinbefore described water miscibleorganic solvents can be suitably employed in such dissolution step.However, as has been noted, the presence in such solvent of salts oforganic acids and/or glycols having a molecular weight of less thanabout 70 has been observed to deleteriously affect the stability of thehalogenated amide antimicrobial. Accordingly, it is preferable (in orderto obtain optimum stability in the resulting compositions of the instantprocess) to employ an organic solvent of the hereinbefore described typewhich is substantially free both of salts of organic acids and ofglycols having molecular weights of less than about 70 grams per mole.

In the aforementioned process, it is generally desirable to avoidprolonged exposure of the halogenated amide antimicrobial to the aqueousreaction medium in the absence of the stabilizer in order to preventexcessive loss (i.e., decomposition) of the halogenated amide productprior to stabilization. In addition, the pH adjustment step is alsodesirably accomplished without prolonged delay since the decompositionrate of the halogenated amide antimicrobial is generally pH dependentand since such decomposition rate is typically minimized within theindicated pH range. In addition, since the rate of decomposition of thehalogenated amide antimicrobial increases with increased temperature, itis preferable to conduct the aforementioned individual process steps(and to store, transport and handle the resulting aqueous antimicrobialcompositions) at ambient temperature (e.g., from about 20° to about 25°C.) or less in order to avoid excessive decomposition of theantimicrobial during such operations.

Naturally, in the practice of the aforementioned process, otheringredients such as those described hereinbefore, can also be added tothe aqueous composition either during or after its preparation pursuantto such process.

The practice of the instant invention is further illustrated by thefollowing examples. In such examples all weight percentages are on atotal weight basis unless otherwise indicated. The polyethylene glycol200 employed in such examples is a commercial grade mixture ofpolyethylene glycols having a weight average molecular weight of about200 and commercially available as Polyglycol E-200 from The Dow ChemicalCompany.

EXAMPLE 1--Cyanuric Acid Stabilization of a Composition Comprising2,2-dibromo-3-nitrilopropionamide, Polyethylene Glycol 200 and Water

These experiments illustrate the increased rate of2,2-dibromo-3-nitrilopropionamide (DBNPA) decomposition in the presenceof water. The stabilizing effect of cyanuric acid upon aqueous DBNPAcompositions is also illustrated.

EXAMPLE 1

A 2.5 g portion of 2,2-dibromo-3-nitrilopropionamide (DBNPA) is placedin a 2 oz. amber bottle. To this is added 23.5 g of polyethylene glycol200 (P.E.G. 200), 23.5 g of water and 0.5 g of cyanuric acid.

Control 1

In a second 2 oz. amber bottle is placed 2.5 g of DBNPA and 47.5 g ofP.E.G. 200.

Control 2

In a third 2 oz. amber bottle is placed 2.5 g of DBNPA, 23.75 g ofP.E.G. 200 and 23.75 g of water.

The contents of each of the three bottles are mixed until all of theingredients are dissolved. The dissolution is accompanied by atemperature rise of about 5° C. After the heat of dissolution hasdissipated, the initial DBNPA content is verified by iodometry. Thebottles are then closed with a polyethylene lined cap and placed in aconstant temperature oven at 50° C. for accelerated decompositiontesting. The samples are removed periodically and the extent of DBNPAdecomposition is determined by iodometry. The results of the accelerateddecomposition testing are presented in Table I below.

In this example (and in the subsequent examples), the relative DBNPAcontent of the various antimicrobial compositions is determined byiodometry. In such test method, an excess of potassium iodide (KI) isadded to the antimicrobial composition and the amount of elementaliodine which has been liberated from the KI (via oxidation of the KI bythe DBNPA) is determined by titration with a standard solution of sodiumthiosulfate. The amount of DBNPA present in the composition tested isthen calculated on the basis of the amount of elemental iodine liberatedthereby.

It should be noted that since certain of the intermediate decompositionproducts of DBNPA are also oxidizing agents, the indicated test methoddoes not, strictly speaking, provide an exact measure of DBNPA content.However, such test method does provide a measure of the amount of DBNPAwhich has completely decomposed to the ultimate non-oxidizing speciesand thus provides a relative measure of the stability of the DBNPAcompositions tested.

                                      TABLE I                                     __________________________________________________________________________     DBNPA CONTENTS AFTER VARIOUS STORAGE PERIODS AT 50° C.                Composition.sup.1                                                                                         Initial                                                                            DBNPA Content After the                      Example        Stabilizer   DBNPA                                                                              Indicated Storage Period at 50°                                        C. .sup.1                                    Number                                                                              P.E.G. 200                                                                         Water                                                                             Type    Amount                                                                             Content                                                                            5 Days                                                                              12 Days                                                                             23 Days                          __________________________________________________________________________    1      47% 47% Cyanuric Acid                                                                         1%   5.15%                                                                              5.08% 4.92% 4.68%                            Control 1*                                                                          95%  None                                                                              None    None 5.0% 4.92% 4.82% 4.62%                            Control 2*                                                                            47.5%                                                                            47.5%                                                                             None    None 5.0% 4.70% 4.22% 3.62%                            __________________________________________________________________________     *Not an example of the invention.                                             .sup.1 The indicated percentages are in weight percent on a total weight      basis.                                                                   

Comparison of Controls 1 and 2 illustrates the adverse effect of waterupon the stability of DBNPA. For example, under aqueous conditions(i.e., Control 2) 28 percent of the DBNPA which was originally presentdecomposes during 23 days at 50° C., i.e., [(5.0-3.62)÷5.0]×100%. Incontrast, the composition of Control 1 (i.e., containing substantiallyno water) suffers a loss of only 8 percent of the DBNPA originallypresent) over the same time period at 50° C., i.e.,[(5.0-4.62)÷5.0]×100%. Similar differences in DBNPA decompositionbetween Control 2 and Control 1 are reflected at the shorter testintervals.

The stabilizing effect of the cyanuric acid in the aqueous compositionis observed by comparing Example 1 with Control 2. Such comparison showsthat the composition of the invention exhibits substantially less DBNPAdecomposition (i.e., substantially more retained DBNPA) after eachstorage interval than does the composition of Control 2 after that samestorage interval.

EXAMPLE 2--Aqueous Solution of 20% DBNPA in P.E.G. 200 Stabilized withCyanuric Acid

Pursuant to the procedure of Example 1, an aqueous antimicrobialcomposition is prepared according to the following recipe:

Dbnpa--10 g

P.e.g. 200--19.5 g

Water--19.5 g

Cyanuric Acid--1.0 g*

The solution is stored in an oven at 50° C. and the DBNPA content isdetermined after 12 days of storage and after 23 days of storage.

The solution of Example 2 is found to contain 19.7 percent DBNPA and19.1 percent after 12 and 23 days, respectively. This representsdecomposition of only 1.5 percent and 4.5 percent of the initial DBNPAover those respective time periods.

EXAMPLE 3--Aqueous Solution of DBNPA in P.E.G. 200 Stabilized with2-chloro-4,6-bis(ethylamino)-s-triazine

Pursuant to the procedure of Example 1, a solution containing thefollowing ingredients is prepared, stored at 50° C. and analyzed forDBNPA content as a function of storage time.

Dbnap--2.5 g

P.e.g. 200--23.5 g

Water--23.5 g

2-chloro-4,6-bis-(ethylamino)-s-triazine--0.5 g*

After 30 days of storage at 50° C., the solution is found to contain 4.2weight percent DBNPA on a total weight basis. This representsdecomposition of only 16 percent of the DBNPA originally present.

In contrast, a solution containing 5 weight percent DBNPA, 47.5 weightpercent P.E.G. 200 and 47.5 weight percent water which is prepared,stored and analyzed in the same fashion is found to contain only 3.4weight percent DBNPA after the same storage period. This DBNPA contentrepresents decomposition of 32 percent of the DBNPA initially present.

Thus, the 2-chloro-4,6-bis(ethylamino)-s-triazine is seen to prevent 50percent of the DBNPA decomposition which otherwise occurs over 30 daysat 50° C.

EXAMPLES 4 and 5--Stabilization of Aqueous DBNPA Compositions withCyanoguanidine and with Succinonitrile

Pursuant to the procedure of Example 1 two compositions are prepared,each containing 2.5 parts by weight DBNPA, 23.5 parts by weight P.E.G.200 and 23.5 parts by weight water, are stabilized with 0.5 parts byweight of cyanoguanidine and with 0.5 parts by weight succinonitrilerespectively. Such compositions are stored at 50° C. and analyzed forDBNPA content as a function of storage time.

In a similar fashion a non-stabilized composition (i.e., Control 4)containing 2.5 parts by weight DBNPA, 47.5 parts by weight P.E.G. 200and 47.5 parts by weight water is prepared, stored and analyzed forcomparison.

The results for the three compositions are presented below.

    ______________________________________                                                        DBNPA Content After the                                                       Indicated Storage Period                                                        11     15     25   28   35                                         Stabilizer Days   Days   Days Days Days                                ______________________________________                                        Example 4                                                                              1 wt. % Cyano-                                                                guanidine    --     4.6  4.4  --   3.9                               Example 5                                                                              1 wt. % succino-                                                              nitrile      4.7    --   --   4.3  --                                Control 4*                                                                             None         4.3    4.0  3.6  3.5  3.2                               ______________________________________                                         *Not an example of the invention.                                        

As is apparent from the foregoing data, the stabilized compositions ofthe invention exhibit substantially more retained DBNPA than does thenon-stabilized aqueous composition of Control 4.

Pursuant to the foregoing procedure, other compounds (i.e., cyanuricchloride, isonicotinic acid hydrazide, nicotinic acid,2,4,6-tri(2-hydroxyethyl)-s-triazine and guanidine sulfate) are testedas possible stabilizers in compositions containing 5 weight percentDBNPA, 47 weight percent P.E.G. 200, 47 weight percent water and 1weight percent of the possible stabilizer. In such compositions, none ofthe indicated compounds provided a significant long term stabilizingeffect. In fact, many of such compositions are observed to have beensubstantially destabilized.

While the practice of the invention has been illustrated with referenceto particular embodiments and examples, it should be understood thatsuch embodiments and examples are not intended to limit the scope of theinstantly claimed invention.

What is claimed is:
 1. An aqueous antimicrobial composition having a pHof from about 2 to about 5 and comprising:(a) an alpha-halogenated amideantimicrobial compound of the formula: ##STR3## wherein: X is hydrogen,halogen or a cyano radical;each R group is independently hydrogen, amonovalent saturated hydrocarbon radical or an inertly substitutedmonovalent saturated hydrocarbon radical or the two R groups are jointlya divalent saturated hydrocarbon radical or an inertly substituteddivalent saturated hydrocarbon radical which, taken with the adjacentnitrogen atom, forms a heterocyclic ring having from 4 to about 10 ringmembers; and R₁ is a cyano radical or an amido radical of the formula:##STR4## wherein R is as hereinbefore defined; (b) a water-miscibleorganic solvent in an amount sufficient to dissolve the halogenatedamide antimicrobial, said solvent being a normally liquid polyalkyleneglycol of the ethylene, trimethylene or tetramethylene series or a mono-or di-saturated hydrocarbyl ether thereof; (c) water; and (d) astabilizing amount of an azine or a nitrile stabilizer which isdifferent from the halogenated amide antimicrobial, said stabilizingamount being an amount sufficient to measurably reduce the decompositionof the halogenated amide antimicrobial in the aqueous composition andsaid azine or nitrile stabilizer being a saturated aliphatic or asaturated alicyclic compound containing a moiety of the formula >C═N--,a moiety of the formula --C.tbd.N, or a combination thereof.
 2. Thecomposition of claim 1 wherein the polyalkylene glycol or ether thereofhas a weight average molecular weight of from about 75 to about
 1000. 3.The composition of claim 1 wherein, in the antimicrobial compound:X ishydrogen, bromine or chlorine; each R group is independently hydrogen, amonovalent saturated hydrocarbon radical or an inertly substitutedmonovalent saturated hydrocarbon radical; and R₁ is a cyano radical. 4.The composition of claim 1 wherein, in the antimicrobial compound:X ishydrogen, chlorine or bromine and R₁ is a cyano radical.
 5. Thecomposition of claim 1 wherein the antimicrobial compound is2,2-dibromo-3-nitrilopropionamide.
 6. The composition of claim 1 whereinthe azine or nitrile stabilizer is cyanuric acid,2-chloro-4,6-(ethylamino)-s-triazine, succinonitrile or cyanoguanidine.7. The composition of claim 6 wherein the water-soluble organic solventis polyethylene glycol, having a weight average molecular weight ofabout 200; the antimicrobial compound is2,2-dibromo-3-nitrilopropionamide; and the pH of the aqueousantimicrobial composition is from about 3 to about
 4. 8. The compositionof claim 1 wherein:(a) the antimicrobial compound constitutes from about1 to about 25 weight percent of the total composition; (b) the waterconstitutes from about 20 to about 60 weight percent of the totalcomposition; (c) the water miscible organic solvent constitutes fromabout 25 to about 75 weight percent of the total composition; and (d)the azine or nitrile stabilizer constitutes from about 0.1 to about 5weight percent of the total composition.
 9. A process for preparing theaqueous antimicrobial composition of claim 1 which comprises the stepsof:(a) preparing the alpha-halogenated amide antimicrobial by the acidcatalyzed reaction of the corresponding nonhalogenated amide withhalogen in aqueous solution at a temperature of less than about 40° C.and in the presence of hydrogen halide at a concentration which is lessthan about 20 weight percent on a total weight basis but which issufficient to catalyze the reaction; (b) dissolving the resultingaqueous reaction mixture in the water miscible organic solvent; (c)adding to the reaction mixture of step (a), or to the water miscibleorganic solvent solution of step (b), a stabilizing amount of the azineor a nitrile stabilizer; and (d) adjusting the pH of the product of step(a), (b) or (c) such that the aqueous antimicrobial composition has a pHof from about 2 to about
 5. 10. The process of claim 9 in which the pHadjustment is such that the aqueous antimicrobial composition has a pHof from about 3 to about
 4. 11. The process of claim 9 wherein thehalogenated amide antimicrobial is 2,2-dibromo-3-nitrilopropionamide andthe halogen is bromine; the water-miscible organic solvent ispolyethylene glycol, or a lower alkyl ether thereof, having a weightaverage molecular weight of about 200; and the azine or nitrilestabilizer is cyanuric acid; 2-chloro-4,6-(ethylamino)-s-triazine,succinonitrile or cyanoguanidine.
 12. The process of claim 9 wherein awater-soluble bromate is introduced to the aqueous reaction mediumduring preparation of the halogenated amide antimicrobial; and the pH ofthe aqueous reaction mixture is adjusted to a value of from about 5 toabout 7 by the addition of an alkali metal, or an alkaline earth metal,carbonate or bicarbonate to such reaction mixture following thepreparation of the halogenated amide and prior to the dissolution ofsuch reaction mixture in the organic solvent.
 13. An aqueousantimicrobial composition having a pH of from about 2 to about 5 andcomprising, based upon the total weight of such composition:(a) fromabout 1 to about 25 weight percent of a halogenated amide antimicrobialof the formula: ##STR5## wherein X is hydrogen, chlorine or bromine andeach R is independently hydrogen, an alkyl group of from 1 to about 6carbon atoms or phenyl; (b) from about 5 to about 90 weight percent ofwater; (c) from about 5 to about 90 weight percent of a water-miscibleorganic solvent which is selected from the group consisting ofpolyethylene glycols, trimethylene glycols, tetramethylene glycols andthe mono- and di- phenyl or C₁ to about C₆ alkyl ethers thereof andwhich has a weight average molecular weight of from about 75 to about1000; and (d) a stabilizing amount, in the range of from about 0.05 toabout 10 weight percent, of an azine or nitrile stabilizer selected fromthe group consisting of cyanuric acid,2-chloro-4,6-(ethylamino)-5-triazine, succinonitrile or cyanoquanidine.14. The composition of claim 13 wherein the halogenated amideantimicrobial is 2,2-dibromo-3-nitritopropionamide.
 15. The compositionof claim 14 wherein the water-miscible organic solvent is polyethyleneglycol having a weight average molecular weight of from about 175 toabout
 250. 16. The composition of claim 14 wherein the water-miscibleorganic solvent is polyethylene glycol
 200. 17. A process for preparingthe aqueous antimicrobial composition of claim 15 which processcomprises the steps of:(a) preparing the2,2-dibromo-3-nitrilopropionamide by the reaction of cyanoacetamide withbromine in aqueous solution (1) at a temperature of less than about 40°C., (2) in the presence of HBr at a concentration which is less thanabout 20 weight percent on a total weight basis but which is sufficientto catalyze the reaction and (3) in the presence of an alkali metal oran alkaline earth metal bromate; (b) dissolving the resulting aqueousreaction mixture in the polyethylene glycol having a weight averagemolecular weight of from about 175 to about 250; (c) adding to thereaction mixture of step (a) or to the solution thereof of step (b) astabilizing amount of the azine or nitrile stabilizer; and (d) adjustingthe pH of the product of step (a), (b) or (c) such that the aqueousantimicrobial composition has a pH of from about 2 to about 5.